Stereoisomerism is a well known phenomenon in organic chemistry. By definition, stereoisomers are compounds that have the same molecular formula and connectivity, yet differ in the spatial arrangement of their atoms. Enantiomers represent one class of stereoisomers. Enantiomers are pairs of molecules that exist as nonsuperimposable mirror images of one another. Those compounds which cannot be superimposed on their mirror images are also said to be chiral.
A common feature of most chiral organic compounds is the presence of one or more "stereogenic" or asymmetric carbon atoms within the molecule. This invention describes a method for the preparation of a wide variety of such asymmetric carbon centers with predetermined stereochemistry. This invention also relates to novel intermediates useful in the synthesis of a wide variety of compounds with predetermined chirality.
Enantiomers are identical with respect to certain physical properties, such as their melting and boiling points. However, they may display profound differences in their chemical properties, particularly within biological systems. For example, it is now believed that the teratogenic effects of the notorious tranquilizer thalidomide are due to only one enantiomer of the drug; the other enantiomer is believed to be a safe and useful tranquilizer devoid of teratogenic side effects. Consequently, the preparation of pharmaceutical agents as pure enantiomers, uncontaminated by an enantiomeric impurity, is now an overriding concern within the pharmaceutical industry.
One approach to the synthesis of enantiomerically enriched asymmetric compounds is to employ an asymmetric catalyst. For example, U.S. Pat. Nos. 5,189,177 and 4,943,635 refer to catalysts for the reduction of ketones to form optically active alcohols and are limited to the production of optically active alcohols. Another approach is to employ stoichiometric chiral auxiliaries. An advantage of the use of chiral auxiliaries is that they allow for the facile purification of products to a high degree of diastereomeric purity by contrast, it is often difficult to further enrich the products of a reaction employing an asymmetric catalyst.
Evans and co-workers have developed a method for the synthesis of enantiomerically enriched molecules that employs one of two chiral oxazolidinones as a "chiral auxiliary." [D. A. Evans et al., J. Am. Chem. Soc., 1982, 104 1737]. A chiral auxiliary provides an asymmetric environment that dictates the stereochemical outcome of a reaction in a predictable fashion and which, subsequent to the reaction in question, is ideally removed intact for reuse. Disadvantages of the Evans method include the following: (1) the chiral auxiliary is costly when obtained from commercial suppliers, and is difficult to synthesize; (2) the attachment of the chiral auxiliary is difficult relative to the invention disclosed herein; (3) the key step in the Evans method, the alkylation reaction, is restricted to reactive substrates, e.g., those that are allylic or benzylic, or which deliver a methyl group; (4) the products of the Evans alkylation reaction are less versatile with respect to subsequent transformations versus the invention disclosed herein.
Larcheveque and co-workers have developed a method for asymmetric synthesis that uses ephedrine as a chiral auxiliary. [Larcheveque et al., Tetrahedron Lett., 1978, 3961; Larcheveque et al., J. Organometallic Chem., 1979, 177, 5]. Although ephedrine is less expensive than the oxazolidinone chiral auxiliaries of Evans et al. (1982), the method of Larcheveque et al. is impractical because it employs a highly carcinogenic co-solvent. In addition, the method, as described by Larcheveque et al. does not lead to highly enantiomerically enriched end products.
The present invention discloses the use of pseudoephedrine as a chiral auxiliary for the preparation of a wide variety of highly enantiomerically enriched end products. Both enantiomers of pseudoephedrine are readily available in large quantities at prices making the asymmetric synthesis disclosed herein commercially practical. The disclosed asymmetric synthesis is useful for producing a wide variety of compounds with predetermined chirality that are useful as chemical intermediates. Chiral intermediates synthesized according to the present invention are useful for the preparation of highly enantiomerically enriched pharmaceutical agents.